Carbamazepine (I) and oxcarbazepine (II) are established first-line drugs used in the treatment of epilepsy:

After oral administration to humans, oxcarbazepine (II) is rapidly metabolised to a pharmacologically active 4:1 mixture of the (S) and (R) enantiomers of 10,11-dihydro-10-hydroxy-5H-dibenz/b,f/azepine-5-carboxamide (III):

WO02/096881 discloses a two-step process for the preparation of racemic (III) from carbamazepine. WO 02/092572 discloses a process for preparing a racemic mixture of (III) from oxcarbazepine and further discloses a process for resolving the (S) and (R)-enantiomers of (III) from the racemic mixture. The enantiomers can be used as intermediates in the preparation of (S)-(−)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide and (R)-(+)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide, two single-isomer drugs that may be used to treat epilepsy and other disorders of the central nervous system (Benes et al, U.S. Pat. No. 5,753,646).
WO 2004/031155 discloses a method for the enantioselective preparation of the (S) and (R)-enantiomers of (III) by asymmetric reduction of oxcarbazepine. The asymmetric reduction is carried out in the presence of a ruthenium catalyst and a hydride source. A suitable catalyst may be formed from [RuCl2(p-cymene)]2 and (S,S)—N-(4-toluenesulfonyl)-diphenylethylenediamine (hereinafter referred to as (S,S)-TsDPEN). A mixture of formic acid and triethylamine (in a 5:2 molar ratio) is used as the hydride source. The disclosed process uses a very low substrate:catalyst ratio, i.e. a high amount of catalyst, (e.g. a ratio of 86:1 in example 1). The first major disadvantage of using such a high amount of catalyst is that the residual level of ruthenium metal, a most undesirable contaminant in the product, will be high and difficult to remove, and therefore the product will be unsuitable for use as an active pharmaceutical ingredient (API) or as a late-stage API intermediate. Regulatory guidance for residual metals derived from catalysts exists and the oral concentration limits for ruthenium residues are controlled particularly tightly. The second major disadvantage is that the ruthenium catalyst is expensive. The catalyst system described in WO 2004/031155 is very inefficient, and the cost contribution of the catalyst system alone prevents the process from being economically viable for large-scale manufacturing purposes.
The process disclosed in WO 2004/031155 also uses large quantities of the hydride source (7 equivalents of formic acid and 2.7 equivalents of triethylamine). Commercial sources of the formic acid/triethylamine mixture (triethylammonium formate) are available, but the mixture is expensive. The considerable excess of formic acid used in the process is potentially hazardous as the formic acid can decompose in the presence of the catalyst, causing gradual or spontaneous liberation of carbon dioxide and flammable hydrogen gas as well as causing pressure build-ups inside the reactor vessel. Premature degradation of the hydride source also means that the reduction reaction is slowed down considerably and does not reach full conversion even on prolonged reaction times, making the reaction even less efficient and ultimately providing product of low purity.
In the examples of WO 2004/031155 the crude product obtained by asymmetric reduction of oxcarbazepine is purified by column chromatography over silica gel. Purification by chromatography on scale is slow, expensive and in many cases impractical due to low throughput. The process disclosed in WO 2004/031155 is not suitable for use on a large scale in terms of efficiency and cannot be regarded as an industrially viable manufacturing process in terms of economy.